Abstract Rift Valley fever virus (RVFV), a prototypical Phlebovirus (family Bunyaviridae), belongs to the NIAID Category A list of pathogens and the CDC list of potential bioterrorism agents. RVFV causes a disease that is endemic in sub-Saharan Africa and can emerge in explosive, mosquito-borne epidemics decimating herds of sheep and cattle, resulting in enormous economic losses. In humans, RVFV infection may cause hemorrhagic fever, encephalitis, and retinal vasculitis. Many different mosquitoes, including several native to North America, are competent vectors for RVFV transmission. Thus, the introduction of RVFV into North America would likely cause panic in the general population, and the effects on livestock could have a devastating economic impact. Induction of a humoral immune response against the viral envelope proteins is necessary and sufficient to provide protection against RVFV. Currently, there is no RVFV vaccine suitable for mass human vaccination programs. The MP-12 strain, which was obtained by 12 serial passages of the wild-type RVFV strain ZH548 in the presence of 5-fluorouracil, is markedly attenuated in mice but retains its immunogenicity. However, intraperitoneal inoculation of MP-12 into young mice or SCID mice results in efficient virus replication in the animals? central nervous system. The neuroinvasiveness and neurovirulence potential of MP-12 is a matter of concern when considering the mass vaccination of the general public, especially, in immunocompromised individuals. The present application proposes the development of a novel and safer MP-12-derived vaccine candidate having several mutations that selectively abolish specific functions of viral envelope glycoproteins and cause a higher expression level of neutralizing epitopes in infected cells. We will test the hypothesis that this MP-12-based vaccine candidate exhibits a better safety profile than MP-12 in mice but still retains its immunogenicity and protective efficacy. In this proposal, we will examine its genetic stability in cultured cells and assess its safety, immunogenicity, and protective efficacy by using mouse models.